1. Field of the Invention
This invention relates generally to the pharmacological treatment of hepatitis C virus infection in patients.
2. Description of the Related Art
Hepatitis C virus (HCV) is the putative agent in the majority of cases of post-transfusion acquired hepatitis. Despite improvement in the quality of the blood-donor pool and the implementation of testing of donated blood, the incidence of acute infection among persons receiving transfusions is still significant. Chronic hepatitis develops in at least half the patients with acute HCV infection (representing about 90% of patients with non-A, non-B hepatitis (NANB)), and cirrhosis develops in at least 20% of this group. A variety of drugs have been evaluated with the aim of halting or slowing the progression of HCV-related diseases.
Certain studies have shown α-interferon (IFA) to have positive effects. See U.S. Pat. No. 5,849,696. Interferons are a family of naturally occurring small proteins and glycoproteins produced and secreted by most nucleated cells in response to viral infection as well as other antigenic stimuli. Interferons render cells resistant to viral infection and exhibit a wide variety of actions on cells. They exert their cellular activities by binding to specific membrane receptors on the cell surface.
One of the principal factors which has been found to severely limit the use of interferon has been the fact that it elicits an immunogenic response in the circulatory system. This response being the production of antibodies to the interferon by the host into which they are injected. This effect causes the flu-like symptoms reported as side effects to interferon therapy and also causes the destruction of the interferon thereby requiring larger doses for a therapeutic effect. It has been found that interferon (like other polypeptides used for therapeutic purposes) can be coupled to polymers which are substantially non-immunogenic and retain the substantial proportion of their desired physiological activity. U.S. Pat. No. 6,177,074 discloses a method of treating chronic hepatitis C virus infection by administering 12,000 molecular weight polyethylene glycol conjugated interferon α (“PEG12,000−IFN α”). It was found that this treatment provides improved therapeutic benefits while substantially reducing or eliminating entirely the undesirable side effects normally associated with interferon α treatment regimes.
Another class of polypeptide immune modifiers derived from the thymus gland, the thymosins, has been shown to trigger maturational events in lymphocytes, to augment T-cell function and to promote reconstitution of immune defects. Thymosin alpha 1 (TA1) is a 28 amino acidic polypeptide with a molecular weight of 3100 that has potent immunologic activity, including stimulation of α- and γ-interferon production, increasing macrophage migration inhibitory factor production, inducing expression of T-cell markers, IL-2 receptors, and improving T-cell helper cell activity. The isolation, characterization and use of THNα1 is described, for example, in U.S. Pat. No. 4,079,127.
Thymosin therapy may also be used in combination with interferon therapy, thereby combining the immune system potentiating effect of thymosins with the anti-viral effects of the interferons. This is disclosed in U.S. Pat. 5,849,696.
Various antiviral agents have been used as sole therapy agents in an attempt to treat chronic hepatitis C infection, including acyclovir, vidarabine, and adenine arabinoside. Sole therapy with these antiviral agents generally has been unsuccessful, either because the agent was highly toxic or resulted in some inhibition of viral replication initially, but failed to sustain viral replication inhibition long-term. See e.g. Alexander, G. J. M. et al., American J. Med. (1988), 85-2A: 143–146.
There remains an important need for therapy for hepatitis C that efficiently and with fewer side effects attacks the virus and modulates the immune response system and reduces the frequency of relapse.